δ-Opioid Receptor Antagonist Inhibits Immunomodulation by Met-Enkephalin Analogs

Abstract

The methionine-enkephalin (Met-enkephalin, Tyr-Gly- Gly-Phe-Met) analogs Tyr-D-Ala-Gly-MePhe-Met NHC₃H₇- iso (1) and Tyr-D-Ala-Gly-MePhe-Gly-NHC₃H₇-iso (2) have been shown to enhance human T cell proliferation in in vitro treatment. Their immunomodulatory activities were completely blocked by naloxone, an opioid antagonist. Now we demonstrate that a selective δ-opioid receptor antagonist, ICI-174,864, completely blocks enhancement of T cell proliferation by analogs (1) and (2). The T cell-stimulatory effect was only partially inhibited by the µ-receptor-selective antagonist, β-funaltrexamine hydrochloride. The κ-opioid receptor antagonist, nor-binaltorphimine dihydrochloride, showed no effect on T cell-proliferation stimulated by analogs (1) and (2). These observations suggest that analogs (1) and (2) of Met-enkephalin stimulate T cell proliferation predominantly via δ-opioid receptor present on T cells.

Damage of Splenic T Lymphocyte Proliferation and Differentiation and Its Normalization by Electroacupuncture in Morphine‐Dependent Mice Mode

“…On the contrary, systemic (intraperitoneal; i.p.) administration of [Met5] enkephalin with small dose (2.5 mg/kg) could increase the T lymphocyte proliferation [15], and selective δ opioid receptor antagonist, ICI-174,864 could block enhancement of T lymphocyte proliferation by [Met5] enkephalin analogs [16]. Therefore, consequences about the lymphocyte proliferation maybe related with the kinds of opioid receptors activated.…”

Opioids As Modulators of Cell Death and Survival—Unraveling Mechanisms and Revealing New Indications

“…The latter effect was shared by Met-enkephalin and inhibited with the DOR-specific antagonist naltrindole (Shahabi et al, 1996), indicating that this effect was probably mediated through the ␦ receptor. Met-enkephalin also stimulated T-cell proliferation (Singh et al, 1999) probably by activating Erk-signaling pathways (Sharp et al, 1998b;Shahabi et al, 1999;Kramer et al, 2002); however, it induced apoptosis in leukemia cells (Mernenko et al, 1996). Dynorphin A, a specific KOR agonist (Chavkin et al, 1982), enhanced the mitogen-induced proliferative response and interleukin-2 production of rat splenocytes.…”

Immunomodulation by Opioid Peptidomimetic Compound

“…The identification of endogenous peptide ligands for these opioid receptors has provided leads for designing receptorselective, biologically stable peptide molecules. The classical approach of replacement of amino acids has provided various opioid peptides with enhanced receptor selectivity and enhanced potency [12][13][14].…”